The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be or to describe prior art to the invention.
Cell to cell communication is imperative for physiological and pathological processes associated with multicellular organisms. This is particularly true for angiogenesis, where the blood vessel endothelial cells require signals generated from cells in the hypoxic tissue in order to initiate the process of forming new capillaries. The transduction of signals from the extracellular milieu of the endothelial cell to the nucleus is a receptor-mediated event. Some of the receptors that mediate critical events in angiogenesis are receptor tyrosine kinases (RTKs). Receptor tyrosine kinases, also known as growth factor receptors, are a family of transmembrane proteins with a large extracellular ligand binding domain, a transmembrane domain, and an intracellular domain with intrinsic tyrosine kinase activity. (See also, Plowman, et al., DN&P 1994, 7, 334-339).
One of the results of tyrosine kinase signal transduction is cell proliferation. Normal cell proliferation is a key physiological process in healthy organisms. However, a number of diseases and disorders are the result of dysfunctional cell proliferation. Included in the diseases resulting from abnormal cell proliferation are blood vessel proliferative disorders referred to as angiogenesis and/or vasculogenesis.
Angiogenesis refers to the process of new capillary formation into tissue or organs and occurs in a number of physiological processes, both normal and pathological. Normal angiogenesis is associated with corpus luteum formation, and fetal and embryonic development. A number of serious diseases are associated with persistent, unregulated angiogenesis. These diseases are dominated by abnormal neovascularization. Included in the diseases in which unregulated angiogenesis is present are rheumatoid arthritis and endometriosis.
Arthritis is a serious health care problem. Progressive arthritic conditions in humans cause severe pain, loss of joint mobility and disfigurement, and an overall reduction in the quality of life. In rheumatoid arthritis, the synovium hyperproliferates (aided by new blood vessels) and invades the cartilage which is destroyed. Conventional treatment for rheumatoid arthritis includes non-steroidal anti-inflammatory drugs (NSAEDs). A need exists for an effective treatment for rheumatoid arthritis that will disrupt disease progression in addition to suppression or amelioration of symptoms. Inhibition of new capillary formation could lessen the joint destruction that occurs in rheumatoid arthritis and halt disease progression.
Endometriosis, the presence of functional endometrium outside of the uterine cavity, is a common disease, causing abdominal pain, dysmenorrhea, dyspareunia and infertility in about 10% of the female population. It is believed to arise from the implantation and growth of exfoliated menstrual endometrium on the peritoneal and ovarian surfaces (Thomas & Prentice, Reprod. Med. Rev., 1992, 1, 21-36). Active endometriotic explants have pronounced vascularization both within and around the tissue (Nisolle, et al., Fertil. Steril., 1993, 59, 681-684), due to the development of new blood vessels through angiogenesis. Current therapeutic strategies range from observation in mild cases to a complete hysterectomy in painful or advanced cases, and includes treatment with hormones to modulate the steroidal support assumed to be needed for the maintenance of ectopic endometrium (Lu & Ory, Mayo Clin. Proc., 1995, 70, 453-463). However, hormone treatments-are not ideal and are not curative (Shaw, Drug Safety, 1994, 11, 104-113). New treatments that are more effective and have fewer side-effects are needed.
Despite the significant progress that has been made in developing treatments for angiogenic diseases and disorders, there remains a need in the art for new methods of treatment.